International Consortium to Identify Genes and Interactions Controlling Oral Clef

描述（由申请人提供）：唇裂，包括唇裂（CL）、唇腭裂（CLP）和腭裂（CP），是人类最常见的先天缺陷之一。口腔唇裂的病因复杂而多样，遗传和环境因素都有强有力的证据。候选基因研究和全基因组连锁研究已经得出了令人信服但不一致的证据，表明多个基因控制着唇腭裂的风险，一些研究显示了基因与环境暴露，特别是母亲吸烟和营养物质之间相互作用的证据。我们已经组建了一个由经验丰富的调查人员组成的联盟，他们已经积累了大量的病例及其家庭（主要是病例-父母三人组）的DNA样本，这些样本现在可用于全基因组研究，这代表了唇腭裂基因调查的下一个水平。具体目标是：1.；利用单核苷酸多态性（SNP）标记的高通量基因分型，对2000例分离的、非综合征性口腔唇裂（CL、CLP或CP）及其父母进行全基因组分析，以检测连锁和LD。初步分析将包括基因效应的个体测试，适当的单倍型分析和对较大染色体区域的新定位方法，允许人群之间的异质性。2. 测试基因与常见的母亲暴露之间的相互作用，包括维生素补充、吸烟和饮酒（通过访谈收集），这些暴露被认为是唇裂的环境风险因素。从单一成分人群（犹他州）获得的营养状况血清生物标志物的可用性为进一步测试GxE相互作用提供了重要的条件。3. 为了测试基因之间的相互作用，这可能解释文献中关于控制唇裂风险的基因的一些相互矛盾的结果。这一建议提供了一个独特的机会来扩大和扩展对控制口唇裂风险的基因的搜索，创造了在人群中快速复制的机会，并将指导进一步的控制正常颅面发育的基因的分子研究。

DESCRIPTION (provided by applicant): Oral clefts, which include cleft lip (CL), cleft lip and palate (CLP) and cleft palate (CP), and collectively represent one of the most common birth defects in humans. Oral clefts have a complex and heterogeneous etiology, with strong evidence for both genetic and environmental causal factors. Candidate gene studies and genome wide linkage studies have yielded compelling but inconsistent evidence that multiple genes control risk to oral clefts, and several studies have shown evidence for interaction between genes and environmental exposures, especially maternal smoking and nutrients. We have assembled a consortium of experienced investigators who have accumulated a very large collection of DNA samples on cases and their families (mostly case-parent trios) that are now available for genome wide studies, which represents the next level of genetic investigation for oral clefts. Specific aims are: 1. To conduct a genome wide analysis on 2000 case-parent trios ascertained through a case with isolated, non-syndromic oral cleft (CL, CLP or CP) and their parents using high throughput genotyping of single nucleotide polymorphic (SNP) markers to test for linkage and LD. The initial analysis will consist of individual tests for gene effects, with appropriately haplotype analysis and novel mapping approaches for larger chromosomal regions that allows for heterogeneity among populations. 2. To test for interaction between genes and common maternal exposures including vitamin supplementation, cigarette smoking and alcohol consumption (collected by interview) which have been implicated as environmental risk factors for oral clefts. Availability of serum biomarker measures of nutritional status from one component populations (Utah) allows important further tests for GxE interactions. 3. To test for interaction between genes that may explain some of the conflicting results in the literature with regard to genes controlling risk to oral clefts. This proposal offers a unique opportunity to expand and extend the search for genes controlling risk to oral clefts, creates the opportunity for quick replication across populations and will direct further molecular studies of genes controlling normal craniofacial development.